Penicillin esterification process

ABSTRACT

ONE STEP ESTERIFICATION OF PENICILLINS OR PENICILLIN SULF OXIDES BY COMMINGLING PHOSGENE WITH A LIQUID MIXTURE OF THE PENICILLIN OR PENICLLIN SULFOXIDE ACID OR SALT, THE SELECTED ALCOHOL, A BASE, PREFERABLY A TERTIARY AMINE, AND AN INERT ORGANIC DILUENT TO FORM THE PENICILLIN OR PENICILLIN SULFOXIDE ESTER WHICH ESTERS ARE USEFUL AS INTERMEDIATES IN THE HEAT REARRANGEMENT TO DESACETOXYCEPHALOSPORANATE ESTERS, WHICH DESACETOXYCEPHALOSPORIN ESTERS CAN BE DEESTERIFIED OR CONVERTED TO NEW AND KNOWN DESACETOXYCEPHALOSPORIN ANTIBIOTICS, E.G., CEPHALEXIN.

United States Patent O 3,586,667 PENICILLIN ESTERIFICATION PROCESS Lowell D. Hatfield, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind. No Drawing. Filed Dec. 22, 1967, Ser. No. 692,678 Int. Cl. C07d 99/16, 99/24 US. Cl. 260-239.1 16 Claims ABSTRACT OF THE DISCLOSURE One step esterification of penicillins or penicillin sulfoxides by commingling phosgene with a liquid mixture of the penicillin or penicillin sulfoxide acid or salt, the selected alcohol, a base, preferably a tertiary amine, and an inert organic diluent to form the penicillin or penicillin sulfoxide ester which esters are useful as intermediates in the heat rearrangement to desacetoxycephalosporanate esters, which desacetoxycephalosporin esters can be deesterified or converted to new and known desacetoxycephalosporin antibiotics, e.g., cephalexin.

BACKGROUND OF THE INVENTION (A) Relation to cephalosporin antibiotic products Esters of penicillin and penicillin sulfoxide esters have become of commercial importance lately as intermediates in the heat rearranging of penicillin sulfoxide esters to cor responding desacetoxycephalosporin esters.

US. Pat. No. 3,275,626, issued Sept. 27, 1966, with Robert B. Morin and Billy G. Jackson as inventors, and entitled Penicillin Conversion Via Sulfoxide" discloses and claims a method for preparing desacetoxycephalosporins by heating a penicillin sulfoxide ester under acid conditions. This Morin-Jackson discovery was very im portant in that it showed the way to obtain cephalosporin antibiotics without the necessity for Cephalosporin C and 7-aminocephalosporanic acid, which are the usual precursors for cephalosporin antibiotics. However, the Morin/ Jackson procedure presented practical difliculties for obtaining commercially significant yields of the desired desacetoxycephalosporins.

One of the problems with the Morin/Jackson process was that the ester groups of their penicillin sulfoxide ester reactants could not easily be removed. Robert R. Chauvette and Edwin H. Flynn discovered certain easily cleaved esters of penicillins and penicillin sulfoxides and described in US. patent application Ser. No. 574,311, filed Aug. 23, 1966, now abandoned, a process for preparing them by mixing a chloroformate or bromoformate of the selected alcohol with the penicillin acid or penicillin sulfoxide acid, in a nonaqueous inert solvent and in the presence of a tertiary amine at a temperature between about C. and about 30 C. to form the corresponding carbonic acid anhydride, and then raising the temperature of the resulting carbonic acid anhydride to effect decarboxylation and formation of the corresponding ester of the penicillanic acid or penicillanic acid sulfoxide.

However, the heat rearrangement of penicillin sulfoxide esters by the Morin/Jackson process, or as improved by the use of the Chauvette/Flynn easily cleaved penicillin and penicillin sulfoxide esters produced a mixture of products. Robin D. G. Cooper has recently discovered that the thermal rearrangement of these easily cleavable esters of penicillins and penicillin sulfoxides can be more specifically directed toward the desired corresponding desacetoxycephalosporin esters by conducting the heat rearrangement in certain tertiary carboxamides, ureas, or sulfonamides. These Cooper developments have been 3,586,667 Patented June 22,, 1971 described in US. applications Ser. No. 636,629, Ser. No. 636,593, and Ser. No. 636,592, all filed May 8, 1967, and all now abandoned. All of these discoveries have made the commercial scale production of cephalosporin antibiotics from penicillin starting materials a strong possibility.

As an illustration, there is current interest in converting commercially available penicillin V (phenoxymethyl penicillin) or penicillin G (benzyl penicillin) to desacetoxy Cephalosporin V or desacetoxy Cephalosporin G by the Morin/Jackson penicillin sulfoxide ester rearranging process, as improved by the Chauvette/Flynn easily cleaved esters and the Cooper solvent discoveries. The resulting desacetoxy Cephalosporin V ester or desacetoxy Cephalosporin G ester can be de-esterified by known methods and used as an antibiotic per se. More importantly, these esters can be treated to remove or cleave the phenoxyacetamido or phenylacetamido group and to form the 7-aminodesacetoxy-cephalosporanic acid ester (the so-called 7ADCA nucleus ester), e.g., by treating the desacetoxy Cephalosporin V ester with phosphorous pentachloride or phosphorous oxychloride in the presence of an organic, non-hydroxylated solvent at a temperature of from about 40 C. to about C. in the presence of about 1 equivalent of basic neutralizing agent for from 1 to 1.5 moles of the phosphorus halide to form the iminohalide of the 7-(phenoxyacetamido) desacetoxycephalosporanate ester, treating the imino-halide with an alcohol to form an imino-ester hydrohalide, and then hydrolyzing the imino-ester hydrohalide to form the 7-aminodesace toxycephalosporanate ester (7-ADCA ester), as described for example by R. R. Chauvette in US. application Ser. No. 651,662, filed July 7, 1967. The resulting 7-ADCA ester can be acylated with a selected acylating group to form a cephalosporin ester with more antibiotic potential, either as such, or after removal of the ester group. For example, by reacting the 7-ADCA ester with D-u-aminophenylglycine in a form in which the amino group is protected under known conditions to form a 7-(protected amino D a-aminophenylacetamido)-3-methyl-3-cephem- 4-carboxylate ester, and then removing the amino-protecting group and the ester group by known methods there is formed free 7- D-a-phenylglycylamido desacetoxycephalosporanic acid. This acid is zwitterion (inner salt) or pharmaceutically acceptable cationic or anionic salt forms thereof is a useful antibiotic in combatting infections caused by Gram-positive and Gram-negative microorganisms, including penicillin G-resistant Staphylococcus aureus. This cephalosporin is known by the generic name, cephalexin, and is of special interest since it can be administered orally to obtain effective blood levels of the antibiotic. Daily doses of from about 1 to about 6 g. of cephalexin per day for a patient of about 70 kilogram weights are usually recommended for therapeutic administration. And all of this is accomplished without the necessity of using fermentation derived Cephalosporin C and 7-aminocephalosporanic acid.

(B) Problems of penicillin and penicillin sulfoxide ester formation Several prior esterification methods for preparing penicillin and penicillin sulfoxide esters have been considered.

(l) A strong acid catalyzed esterification of the penicillin acid or penicillin sulfoxide acid with the selected alcohol gives poor results. The penicillin nucleus generally does not survive such strong acid treatment, and hence the yield of the desired ester by this method is most always lower than desired.

(2) A carbodiirnide esterification of penicillins and penicillin sulfoxides suffers the disadvantage that the product is a difficultly separable mixture of the desired penicillin or penicillin sulfoxide ester and an acyl urea by-product which ties up a portion of the penicillin starting material, and thus lowers the yield of penicillin or penicillin sulfoxide ester.

(3) The reaction of a penicillin or penicillin sulfoxide with the chloroformate or bromoformate of the selected alcohol in the presence of a base, as described above, is an effective esterification method, but this method is dependent upon the separate preparation and purification of the haloformate starting material and thus involves an expensive procedure.

Thus, there is a need in this developing penicillin conversion technology for a simplified, economical process or method for preparing these vital penicillin and penicillin sulfoxide ester intermediates, and it is the primary object of this invention to satisfy that need.

A further object of this invention is to provide a onestep process or method for esterifying penicillin and penicillin sulfoxide acid materials to form penicillin and penicillin sulfoxide ester products which are useful as intermediates in the heat-rearrangement of penicillins to desacetoxycephalosporin esters, which esters may be deesterified to corresponding desacetoxycephalosporanic acid antibiotics, or converted by known methods to more highly active desacetoxycephalosporin compounds.

A further object of this invention is to contribute a process improvement for making penicillin and penicillin sulfoxide esters, which are valuable as intermediates in the overall process of converting penicillins to cephalosporin antibiotics, enabling the economical by-passing of the necessity for fermentation derived Cephalosporin C and the 7-aminocephalosporanic acid (7ACA) derived therefrom.

SUMMARY OF THE INVENTION Briefly, according to the process or method of this invention phosgene is commingled with a liquid mixture of the selected penicillin or pencillin sulfoxide acid, the selected alcohol, and a tertiary amine or equivalent hydrogen halide absorber in an inert organic diluent at temperatures low enough to control the exothermic reaction which takes place and thus to avoid any substantial degradation of penicillin ester products, or reactants.

DETAILED DESCRIPTION OF THE INVENTION More specifically, it has been found according to this invention that by commingling phosgene (carbonyl chloride) with a solution of the penicillin acid and alcohol reactants, mixed with an appropriate hydrogen halide absorber, usually a base, such as pyridine, or other tertiary amine in an inert organic liquid diluent at a temperature not above about 40 C., the desired corresponding penicillin or penicillin sulfoxide ester is formed in good yield in easily recoverable form. The phosgene may be added to the penicillin acid or penicillin sulfoxide acid containing mixture, in solution of an organic solvent such as acetone, or the phosgene and the penicillin acid or penicillin sulfoxide acid mixture may be concurrently mixed in suitable plant scale equipment designed to quickly remove heat of reaction and/ or to Operate the process in a continuous manner. The penicillin acid or penicillin sulfoxide and alcohol and base should not be added to the phosgene in undiluted form, however. Conducting the process in this invention may involve an in situ formation of the carbonic acid anhydride or the pencillin acid chloride, but contrary to the disadvantages of some of the prior art methods, each of these two possible intermediates is desirable for penicillin ester formation, and in addition, as a result of this invention it becomes unnecessary to separately prepare haloformate reactants. Any excess phosgene used in the process is readily neutralized by the excess base present in the mixture, or destroyed by the water which is added after the phosgene addition is completed. The water or other separating medium which may be used precipitates the penicillin ester product, which crude precipitated product may be readily separated from the reaction mixture in conventional manner.

In place of phosgene, carbonyl bromide, thiophosgene, carbonyl fluoride, or other equivalent reagents may be used, but for economical reasons phosgene is preferred.

The esterification reaction is conducted in the presence of a hydrogen halide absorber or acid acceptor substance which is preferably an inexpensive tertiary amine which is soluble in the organic liquid diluent, but inexpensive alkali metal bicarbonates such as the lithium, sodium, and potassium bicarbonates could be used. Examples of inexpensive hydrogen halide absorbers include the trialkylamines, such as the C to C trialkylamines, e.g., trimethylamine, tributylamine, dimethylbutylamine, and the heterocyclic amines such as pyridine, quinoline, the picolines, lutidines, and the like, the N,N-di-lower alkylanilines such as N,N-dimethylaniline, N,N-diethylaniline, and the like.

Organic liquid diluents which may be used include the common aromatic solvents such as benzene, toluene, and the xylenes, the halogenated lower aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, lower alkanones such as acetone, methyl ethyl ketone, and the like, lower acyl nitriles such as acetonitrile, propionitrile, and the like, as well as lower dialkylsulfoxides such as dimethylsulfoxide, diethylsulfoxide, the lower dialkylacylamides such as dimethylformamide, diethylformamide, ethers such as dioxane, tetrahydrofuran, diethyl ether of diethylene glycol, lower nitro-hydrocarbons such as nitromethane, nitropropane, and the like, and alkyl acylates having up to about 7 carbon atoms, e.g., ethyl acetate, propyl acetate, and organic liquid diluent mixtures, such as dioxane-acetone, dimethylsulfoxidebenzene, and the like. The organic liquid diluent is inert in that it does not interfere significantly with the esterification reaction. The diluent is also preferably water miscible so that the reaction mixture mixes nicely with the water which is added after phosgene addition is completed. A substantially anhydrous liquid medium is preferred for economic reasons but a small amount of water in the system can be tolerated without serious interference. However, it is desirable to keep the Water content in the reaction system below about 5 percent, preferably below about 2.5 percent, since the presence of water necessitates the use of excess base and solvent in the system. Excess alcohol could be used as the organic liquid diluent but is not preferred since the excess alcohol competes for the added phosgene to form side-reaction products, thus involving waste of reactants. The common inert organic liquid diluent for the process of this invention will be selected by those skilled in the art primarily on the basis olflcost and availability. Numerous such diluents are availa e.

The penicillin and penicillin sulfoxide acid starting materials are those which have one of the following general formulas:

penicillin sulfoxide acid where R is hydrogen or the residue of an acyl group of the particular penicillin. The alkali metal salts of these penicillins such as the sodium and potassium salts can also be used. For reasons of availability and cost phenoxymethyl penicillin, as such, or in its sulfoxide form are preferred. However, it is to be understood that there are literally thousands of penicillins in the prior art to which the process of this invention is applicable in making penicillin and penicillin sulfoxide esters for conversion to corresponding desacetoxycephalosporanate esters in the overall process of converting penicillins to specific cephalosporin antibiotics. If desired, this process can also be applied to the penicillin nucleus (6-APA), if the 6-amino group is suitably protected by known methods.

Numerous penicillins derived by fermentation methods known in the prior art (e.g., those penicillins disclosed in Behrens et al. US. Pats. 2,479,295 to 2,479,297 which issued Aug. 16, 1949; 2,562,407 to 2,562,411 which issued July 31, 1951, and 2,623,876 which issued Dec. 30, 1952) can be esterified by the method of this invention or first converted to the sulfoxides and esterified by the method of this invention. For practical considerations, the preferred penicillin and penicillin sulfoxide acids for use in the process of this invention are those of the formulas:

CH3 R-g-NH-CHC o om O=(|J-NCOOH wherein R in each formula is phenyl, benzyl, phenoxymethyl, phenylmercaptomethyl, and such groups substituted with chlorine, methyl, methoxy, trifiuoromethyl, or nitro groups, as well as heptyl and thiophene-Z-methyl. Penicillins with these representative R groups are examples of the most economically prepared or more readily obtainable by fermentation methods. The penicillin esters prepared by the method of this invention are useful as intermediates to desacetoxycephalosporin antibiotics in that they can be oxidized by known methods, e.g., with 3-chloroperbenzoic acid, to form the corresponding penicillin sulfoxide esters which can be heat rearranged to the corresponding desacetoxycephalosporanate ester as described above.

The ester products of the invention and desacetoxycephalosporins obtained therefrom are conveniently named by useing the penam and cepham nomenclature system. The penam nomenclature system for the penicillins is described by Sheehan, Henery-Logan, and Johnson in the J. Am. Chem. Soc., 75, p. 3293, footnote 2 (1953), and has been adapted to the cephalosporins by Morin, Jackson, Flynn and Roeske in the J. Am. Chem. Soc. 84, 3400 ,(1962). In accordance with these systems of nomenclature penam and cepham refer respectively to the following saturated ring system:

while cepham" refers to the same corresponding ring cepham structure but containing a double bond, the position of which is indicated by the lowest numbered carbon atom to which the double bond is connected, or by the word delta with a superscript for the same carbon atom number designation. Thus, for example, penicillin V (phenoxymethyl penicillin) can be named 6-(phenoxyacetamido)-2,2-dirnethylpenam-3-carboxylic acid. Similarly, a 2,2,2-trichloroethyl penicillin V sulfoxide ester obtained therefrom with 2,2,2-trichloroethanol can be named 2,2,2-trichloroethyl 6-(phenoxyacetamido)-2,2- dimethylpenam-3-carboxylate. Other examples of penicillin and penicillin sulfoxide ester products which can be prepared by the process of this invention include:

4 methoxybenzyl 6-(phenylacetamido)-2,2-dimethylpenam-3-carboxylate-l-oxide from 4-methoxybenzyl alcohol and benzyl penicillin sulfoxide acid,

Benzyloxymethyl 6 (phenylmercaptoacetamido)-2,2- dimethylpenam-3-carboxylate from benzyloxymethanol and phenylmercaptomethyl penicillin,

4 methoxyphenyl 6 (octanoylamido)-2,2-dimethyl penam-3-carboxylate-l-oxide from 4-methoxyphenol and heptyl penicillin sulfoxide,

2,2,2 trichloroethyl 6-(thiophene-2-acetamidoT-2,2-dimethylpenam-3-carboxylate from 2,2,2-trichloroethanol and thiophene-methyl penicillin,

Bis(4 methoxyphenyl)methyl 6-(3'-chlorophenylacetamido) 2,2-dimethylpenam-3-carboxylate-1-oxide from bis(4-methoxyphenyl) methanol and 3-chlorobenzyl penicillin sulfoxide,

3 methoxybenzyl 6-(2',4,6-trimethylphenoxyacetamido) 2,2-dimethylpenam-3-carboxylate from S-rnethoxybenzyl alcohol and 2,4,6-trimethylphenoxymethyl penicillin;

Benzyl 6-(3',5'-dichlorophenylmercaptomethyl)-2,2- dimethylpenam-3-carboxylate-l-oxide= from benzyl alcohol and 3,5 dichlorophenylmercaptomethyl penicillin sulfoxide;

2 methoxybenzyl 6-(4'-trifluoromethylphenylacetamido) 2,2-dimethylpenam-3-carboxylate from Z-methoxybenzyl alcohol and 4-trifiuoromethylbenzyl penicillin;

4 methoxybenzyl 6 (3,4-dimethylphenylmercaptoacetamido) 2,2'-dimethylpenam 3-carboxylate-l-oxide from 4-methoxybenzyl alcohol and 3,4-dimethylphenylmercaptomethyl penicillin sulfoxide;

Benzhydryl 6 (3-trifluorornethylphenoxyacetamido)- 2,2-dimethylpenam-3-carboxylate from benzhydryl alcohol and 3-trifluoromethylphenoxyrnethyl penicillin;

4 methoxybenzyl 6-(4-nitrophenylacetamido)-2,2-dimethylpenam-3-carboxylate-l-oxde from 4-methoxybenzyl alcohol and 4-nitrobenzyl penicillin sulfoxide; and

Bis(3,5 dimethoxyphenyl)methyl 6-,(3',4-dimethylphenylacetamido) 2,2 dimethylpenam -3-carboxylatel-oxide from bis(3,S-dimethoxyphenyDmethyl alcohol and 3,4-dimethylbenzyl penicillin sulfoxide;

Benzhydryl 6 4'-methylphenylacetamido) -2,2,-dimethylpenam-3-carboxylate from benzyhydryl alcohol and 4- methylbenzyl penicillin;

3,5 dimethoxybenzyl 6 4' nitrophenoxyacetamido), 2,2 dimethylpenam 3 carboxylate 1 oxide from 3,5-dimethoxybenzyl alcohol and 4-nitrophenoxymethyl pencillin;

Tert-butyl 6 (phenoxyacetamido),2,2-dimethylpenam- 3-carboxylate from tert-butyl alcohol and penicillin V;

Phthalimidomethyl 6 (phenylacetamido) 2,2 dimethylpenam 3 carboxylate-l-oxide from phthalimidomethyl alcohol and penicillin G. sulfoxide;

Succinimidomethyl 6 (3 chlorophenoxyacetamido), 2,2-dimethylpenam 3 carboxylate from succim'midomethanol and 3 chlorophenoxymethyl penicillin;

Benzyl 6-(4' methylphenylacetarnido) 2,2-dimethylpenam-B-carboxylate-1-oxide from benzyl alcohol and 4-methylbenzyl penicillin sulfoxide potassium salt.

The selected alcohol for penicillin or penicillin sulfoxide ester formation may be any alcohol which forms a readily cleavable penicillin ester group after the heat conversion step or one which forms an orally antibiotically active desacetoxycephalosporanate ester. Preferred easily cleaved esters are, for example, those obtained from 2,2,2-trichloroethanol, benzyl alcohol, benzyloxymethanol, the methoxy-substituted benzyl alcohols such as 4-methoxybenzyl alcohol, 3-methoxybenzyl alcohol, 3, S-dimethoxybenzyl alcohol, benzhydrol alcohol, bis(4- methoxyphenyl) methanol, and the hydroxmic alcohols such as N-hydroxysuccinimide, N-hydroxyphthalimide, as well as phthalimidomethyl alcohol and succinimidomethyl alcohol. Some cephalosporin antibiotics in the acetoxymethyl ester form are orally absorbed, such as the acetoxymethyl 7-(2'-thienylacetamido) cephalosporinate. When such an antibiotic is being prepared from penicillin or penicillin sulfoxide ester materials, it will be desirable to use acetoxymethanol as the alcohol. Lower alkanols having from 1 to 6 carbon can also be used, but, in general, they form more difiicultly cleavable esters, and therefore are not preferred.

The addition of phosgene or similar materials to the mixture of the selected penicillin or penicillin sulfoxide acid, or salt, alcohol, hydrogen halide absorber, and organic liquid solvent or diluent causes an exothermic reaction and evolution of carbon dioxide to occur. This exothermic reaction can be controlled to a desirable rate by a variety of known methods. The mixture is generally cooled and stirred or otherwise agitated to distribute the heat of reaction. Also, the rate of addition of phosgene can be controlled to a slow rate to reduce the requirement for extensive cooling equipment. However, it is generally preferred to cool the mixture to which the phosgene is added to from --20 C. to about 40 C., depending upon the size of the reaction mixture and the rate of reaction desired. The low temperatures are generally maintained until all of the phosgene has been added, and the exothermic reaction has subsided.

When the reaction is completed, as indicated by absence of exothermic heat, or cessation of evolution of CO the penicillin or penicillin sulfoxide ester product can be removed from the reaction mixture by adding water in an amount to precipitate the ester product, and to destroy any excess phosgene in the mixture. The crude ester (if it is an oil) can be removed by extraction with an appropriate organic solvent, filtration and purified, e.g., by crystallization of extracted ester, recrystallization of solids obtained from the process, or a slurry of the solids in the appropriate solvent or solvent mixture such as ethyl acetate and chloroform mixtures.

The penicillin or penicillin sulfoxide acid or salt is preferably mixed with a slight molar excess of the selected alcohol in the organic solvent to insure complete reaction of the more expensive penicillin material. An excess of hydrogen halide absorber, such as a tertiary amine, is preferably used to insure complete reaction of the phosgene and its by-products. Care is taken in the equipment used to provide for the release of evolved gases such as carbon dioxide from the reaction mixture.

The invention is further illustrated by the following detailed examples which show the preparation of a penicillin sulfoxide before esterification, and the esterification procedure. 'It is to be understood, however, that it is not required to form the sulfoxide before the esterification procedure, but is only the preferred practice.

EXAMPLE 1 Penicillin V sulfoxide A suspension of 350 g. (1.0 mole) of penicillin V (phenoxymethyl penicillin) in 1 liter of acetic acid was cooled to to C. and 200 ml. of percent hydrogen peroxide in water (about 2 moles of H 0 was added dropwise at 15 to 20 C. over 90 minutes while stirring the mixture. The penicillin V slowly dissolved giving a clear, pale (light) yellow solution. After about 2 hours at 15 to 20 C. the penicillin V sulfoxide began to crystallize from the solution. Stirring was continued for a total reaction time of 4 hours. The mixture was cooled to about 0 C. and 1 liter of water was added dropwise in 60 minutes. The precipitate was filtered, washed with 5 liters of water, and dried for 18 hours at 60 C. There was thus obtained 312 g. (85.5 percent yield) of penicillin V sulfoxide as a white solid, M.P. 167 to 168 C. with dec. The infrared (IR) and nuclear magnetic resonance (NMR) spectra and melting point data were identical with the data of a sample of known penicillin V sulfoxide.

Penicillin V sulfoxide, 2,2,2-trichloroethyl ester A stirred mixture of 366 g. (1 mole) of penicillin V sulfoxide and 166 g. (1.1 moles) of 2,2,2-trichloroethanol in 1 liter of acetone was cooled to 0 to 5 C. and 240 g. (3 moles) of pyridine was added at such a rate that the temperature did not exceed 10 C. Then ml. (about g., 1.4 moles) of phosgene was added dropwise in 30 minutes from a jacketed dropping funnel which was cooled to approximately 50 C. with a Dry Ice-acetone mixture. Carbon dioxide evolution was extremely rapid throughout the phosgene addition. Stirring was continued for an additional 30 minutes at 5 to 10 C. to insure completion of the reaction. Then 2 liters of water was added dropwise in 60 minutes at 0 to 10 C. The precipitate which formed was collected, washed with water, air-dried, and then vacuum dried at 65 C. for 2 hours. In this manner there was obtained 402 g. (80 percent yield) of the crude penicillin V sulfoxide ester [2,2,2-trichloroethyl 6-(phenoxyacetamido)-2,2-dimethylpenam 3 carboxylate-l-oxide] as a pale yellow, granular solid, M.P. 141- 143 C. The material was slurried in a mixture of 300 ml. of methyl isobutyl ketone and ml. of ethyl ether at about 0 C., collected, washed with a cold 1.5 :1 volume mixture of methyl isobutylzethyl ether, and dried, yielding 358 g. (71.5 percent yield) of the cleaner 2,2,2- trichloroethyl' penicillin V sulfoxide ester, M.P. 146 to 148 C. The ester was identical, by mixed melting point, IR and NMR analyses with a known sample of the penicillin V sulfoxide ester.

I COOK A suspension of 37.2 gr. (0.10 mole) of penicillin G potassium salt in 150 ml. of acetone was cooled to approximately 0 C. To this cooled suspension was added 16 gr. (0.11 mole) of 2,2,2-trichloroethanol and then 18 gr. (0.22 mole) of pyridine. The mixture was stirred and 14 gr. (about 0.14 mole) of phosgene was added over 45 minutes at 0-5 C. Stirring was continued for 10 minutes and then 300 ml. of cold water was added in 20 minutes. The oil that separated was extracted with 500 ml. of ethyl acetate. The organic layer containing the ester product was washed with 5 percent sodium bicarbonate solution, and then with 100 ml. of 5 N hydrochloric acid. After separating the organic phase from the aqueous phase, the organic phase was dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the residue was triturated with 400 ml. of ethyl ether. The white solid produced was collected, washed with ether, and dried, yielding 32.7 g. (70 percent yield) of the 2,2,2-trichloroethyl penicillin G ester [2,2,2-trichloroethyl 6-(phenylacetamido) 2,2 dimethylpenam-3-carboxylate], M.P. 159- 160 C. Infrared (IR) and nuclear magnetic resonance (NMR) spectra of this product were identical with the same ester made by the carbodiimide method.

9 EXAMPLE 3 The 4-methoxybenzyl penicillin V sulfoxide ester [4- methoxybenzyl 6 (phenoxyacetamido)-2,2-dimethylpenam-B-carboxylate-l-oxide] was prepared in a manner similar to that described in Example 1, using 4-methoxy=benzy1 alcohol instead of 2,2,2-tIichloroethanol.

The oil that separated after the addition of water was extracted with 100 ml. of chloroform, and the organic layer containing the ester product was washed with percent sodium bicarbonate solution, 100 ml. of 1.1 N hydrochloric acid, and 100 ml. of water. The chloroform solution was dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. The viscous, yellow oil residue was treated with 500 ml. of ether. The yellow, granular solid was collected, washed with ether and dried to give 21.6 gr. (45 percent yield) of the 4-methoxybenzyl penicillin V sulfoxide ester, M.P. 126-129" C. The IR and NMR spectra for this product were identical with a sample of the same ester made by esterifying the penicillin V acid with 4-methoxybenzyl bromide.

EXAMPLE 4 O T S A suspension of 36.6 gr. (0.10 mole) of penicillin V sulfoxide in 100 ml. of acetone was added to a 500 ml., round bottomed, three-necked flask equipped with a stirrer, thermometer, Dry Ice-acetone condenser, and inlet tube for phosgene gas addition. The mixture was cooled and stirred in this container to 0 C. and then 24 gr. (0.3 mole) of pyridine was added, followed by 10.8 gr. (0.10 mole) of benzyl alcohol. Gaseous phosgene, 12.0 gr. (0.12 mole) was introduced dropwise via the inlet tube from a liquid reservoir containing the desired weight of phosgene. The addition required about 30 minutes during which time the temperature was maintained at 0-5 C. Stirring was continued for 10 minutes until carbon dioxide evolution ceased. Then 150 ml. of ice cold water was added in minutes. The white solid produced was collected, washed with cold 1.5:1 water:acetone mixture, then air dried and then vacuum dried at 60 C. for 4 hours yielding 40.6 gr. (89 percent yield) of the benzyl ester of penicillin V sulfoxide, M.P. 118-120 C. The IR and NMR spectra for this product were identical with that of a sample of the same ester prepared via the benzyl chloroformate route.

I claim:

1. A process for preparing an ester of a penicillin or pencillin sulfoxide which comprises commingling phosgene with a liquid mixture of (a) the penicillin or penicillin sulfoxide in the acid form or an alkali metal salt thereof,

(b) the alcohol corresponding to the desired penicillin or penicillin sulfoxide ester, and

(c) a hydrogen halide absorbing base, in

(d) an inert organic liquid diluting medium at a temperature not above about 40 C. to form the corresponding penicillin or penicillin sulfoxide ester.

2. A process which comprises commingling phosgene with a liquid mixture of (a) a penicillin or penicillin sulfoxide in the acid form or an alkali metal salt form thereof, (b) the alcohol corresponding to the desired penicillin or penicillin sulfoxide ester, and (c) a hydrogen halide absorbing base, in an inert organic liquid diluting 10 medium at a temperature not above about 40 C. to form the corresponding penicillin or penicillin sulfoxide ester, wherein the penicillin or penicillin sulfoxide has a formula selected from the group consisting of where R is selected from the group consisting of phenyl, benzyl, phenoxymethyl, phenylmercaptomethyl, such phenyl, benzyl, phenoxymethyl, and phenylmercaptomethyl groups substituted with chlorine, methoxy, methyl, or nitro, and heptyl and thiophene-2-methyl, and the alcohol is selected from the group consisting of 2,2,2-trichloroethanol, benzyl alcohol, tert-butanol, benzyloxymethanol, methoxyphenol, methoxybenzyl alcohol, 3,5- dimethoxybenzyl alcohol, benzhydryl alcohol, and bis- (4-methoxyphenyl)methanol, the hydrogen halide absorbing base is a tertiary amine, and the inert organic liquid diluent is a water-miscible organic diluent.

3. A process as defined in claim 2 wherein phosgene is comrningled with a liquid mixture of (a) phenoxymethyl penicillin sulfoxide, (b) 2,2,2-trichloroethanol, (c) a tertiary amine and an inert organic diluent, at a temperature of from about -20 C. to about 40 C. to form 2,2,2-trichloroethyl phenoxymethyl penicillin sulfoxide ester.

4. A process as defined in claim 2 wherein phosgene is commingled with a liquid mixture of (a) benzyl penicillin, (b) 2,2,2-trichloroethanol, (c) a tertiary amine and an inert organic diluent at a temperature of from about 20 C. to about 40 C. to form 2,2,2-trichloroethyl benzylpenicillin.

5. A process as defined in claim 2 wherein phosgene is commingled with a mixture of (a) phenoxymethyl penicillin sulfoxide, (b) 4-methoxybenzyl alcohol, (0) a tertiary amine, and an inert organic liquid diluent at a temperature of from about 20 C. to about 40 C. to form the 4-methoxybenzyl phenoxymethyl penicillin sulfoxide ester.

6. A process as defined in claim 2 wherein phosgene is commingled with a mixture of (a) phenoxymethyl penicillin sulfoxide, (b) benzyl alcohol, (c) a tertiary amine and an organic liquid diluent at a temperature of from about --20 C. to about 40 C. to form the benzyl phenoxymethyl penicillin sulfoxide ester.

7. In a method of preparing a penicillin or penicillin sulfoxide ester, the improvement which comprises commingling phosgene with a mixture of the penicillin acid or penicillin sulfoxide acid, or an alkali metal salt thereof, the selected alcohol, a tertiary amine, in an inert organic liquid diluent at a temperature not above 40 C. to form the corresponding penicillin or penicillin sulfoxide ester.

8. The improved process as described in claim 7 wherein phosgene is added to a mixture of a penicillin sulfoxide acid of the formula ethanol, benzyl alcohol, tertiary-butanol, benzyloxymethanol, 4-methoxyphenol, 4-methoxybenzyl alcohol, 3,5-dimethoxybenzyl alcohol, benzhydryl alcohol, and bis(4- methoxyphenyl)methanol, a tertiary amine, in a liquid diluent to form the respective penicillin or penicillin sulfoxide ester.

9. The improved process as described in claim 8 wherein phosgene is added to a mixture of penicillin V sulfoxide acid, 2,2,2-trichloroethanol, and a tertiary amine in an organic liquid diluent medium, cooled to from about 20 C. to about 40 C. to form 2,2,2-trichloroethyl phenoxymethyl penicillin sulfoxide ester.

10. The improved process as described in claim 8 wherein phosgene is added to a mixture of penicillin V sulfoxide, 4-methoxybenzyl alcohol, and a tertiary amine, in an inert organic liquid diluent at a temperature of from about 20 C. to about 40 C. to form the 4-methoxybenzyl penicillin V sulfoxide ester.

11. A process which comprises (a) forming a liquid mixture of a penicillin acid or a penicillin sulfoxide acid or an alkali metal salt thereof, the alcohol corresponding to the desired penicillin or penicillin sulfoxide ester, a hydrogen halide absorbing base, in an inert organic liquid diluting medium, (b) comrningling phosgene with the mixture from step (a), while (c) controlling the temperature of the liquid mixture not above about 40 C., to form a penicillin or penicillin sulfoxide ester.

12. A process as defined in claim 11 wherein water is added to the reaction mixture to precipitate the penicillin or penicillin sulfoxide ester product.

13. A process which comprises (a) forming a liquid mixture of a penicillin acid or penicillin sulfoxide acid or an alkali metal salt thereof, the alcohol corresponding to the desired penicillin or penicillin sulfoxide ester, a hydrogen halide absorbing base, in an inert organic liquid diluting medium, (b) commingling phosgene with the mixture from step (a), while (c) controlling the temperature of the liquid mixture not above about 40 C. to form a penicillin or penicillin sulfoxide ester, wherein the penicillin or penicillin sulfoxide has a formula selected from the group consisting of and O=(|JN O-COOH where R is selected from the group consisting of phenyl, benzyl, phenoxymethyl, phenylmercaptomethyl, such phenyl, benzyl, phenoxymethyl, and phenylmercaptomethyl groups substituted with chlorine, methoxy, methyl, or nitro, and heptyl and thiophene-Z-methyl, and the alcohol is selected from the group consisting of 2,2,2- trichloroethanol, benzyl alcohol, tert-butanol, benzyloxymethanol, methoxyphenol, methoxybenzyl alcohol, 3,5- dimethoxybenzyl alcohol, benzhydryl alcohol, and bis- (4-methoxyphenyl)methanol, the hydrogen halide absorbing base is a tertiary amine, and the inert organic liquid diluent is a water-miscible organic diluent.

14. A process which comprises forming a mixture of phenoxymethylpenicillin sulfoxide, pyridine, and 2,2,2-trichloroethanol in acetone, adding phosgene to the mixture while controlling the temperature below about 40 C. to form the 2,2,2-trichloroethyl phenoxymethylpenicillin sulfoxide ester.

15. A process as defined in claim 14 which further includes the steps of adding water to the reaction mixture to precipitate the 2,2,2-trichloroethyl-phenoxymethylpenicillin sulfoxide ester.

16. A process as defined in claim 13 wherein Water is added to the reaction mixture to precipitate the penicillin or penicillin sulfoxide ester product.

NICHOLAS S. RIZZO, Primary Examiner \U.S. Cl. X.R. 424-246, 271 

